Matrix metalloproteinase-2 & progressive cardiac fibrosi

基质金属蛋白酶-2

• 批准号: 6652376
• 负责人: DAVID H LOVETT
• 金额: $ 30.87万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652376
• 关键词: cell proliferation; collagenase; endothelin; fibroblasts; fibrogenesis; fibrosis; gene expression; genetic enhancer element; genetically modified animals; heart cell; heart failure; interleukin 1; laboratory mouse; molecular pathology; protein biosynthesis

DESCRIPTION (provided by applicant): Persistent dysfunctional remodeling of the heart as a response to injury represents a final common pathway resulting in ventricular failure and death. Changes in the proliferative capacity and extracellular matrix synthetic profile of the cardiac fibroblast component of the heart are primarily responsible for these events. These changes in the cardiac fibroblast phenotype are driven by conditions and peptide factors commonly present within the failing heart, including tissue hypoxia and enhanced release of pro-fibrotic peptides, such as angiotensin II, endothelin-1 and Interleukin-1 . Ventricular remodeling is also associated with enhanced synthesis of several matrix metalloproteinases, of which MMP-2 (gelatinase A) may be of central importance. The primary hypothesis of this proposal is that enhanced synthesis of gelatinase A in response to ischemic injury and pro-fibrotic peptides directly drives the dysfunctional changes in cardiac fibroblast phenotypes responsible for progressive cardiac failure. This proposal will examine the transcriptional regulation of gelatinase A in response to angiotensin II, endothelin-1 and Interleukin-1 to define critical enhancer elements and transcription factors that drive high level synthesis of this enzyme in the heart. The validity of these transcriptional regulatory mechanisms will be directly tested in a genomic context using transgenic gelatinase A mice containing defined mutations in specific enhancer elements. Finally, the ability of gelatinase A as an individual agent to induce dysfunctional ventricular remodeling will be tested in vivo using targeted gene expression in the heart. These studies should provide key insights into the role of a specific matrix metalloproteinase in the cardiac response to injury and could provide the pathophysiologic basis for the development of new forms of therapy for this disabling condition.

描述(由申请人提供)： 作为对损伤的反应，心脏持续的功能障碍重构是导致心力衰竭和死亡的最终共同途径。心脏成纤维细胞成分的增殖能力和细胞外基质合成特征的变化是这些事件的主要原因。心脏成纤维细胞表型的这些变化是由衰竭心脏中常见的条件和多肽因素推动的，包括组织缺氧和促纤维化多肽的释放增加，如血管紧张素II、内皮素-1和白介素1。心室重构还与多种基质金属蛋白酶的合成增强有关，其中明胶酶A可能是最重要的一种。这一建议的基本假设是，对缺血损伤和促纤维化多肽的反应导致明胶酶A合成增加，直接导致心脏成纤维细胞表型的功能失调，导致进展性心力衰竭。这项建议将研究明胶酶A对血管紧张素II、内皮素-1和白介素1的转录调节，以确定关键的增强子元件和转录因子 心脏中这种酶的高水平合成。这些转录调控的有效性 这些机制将直接在基因组环境中进行测试，使用含有特定增强子元件的明确突变的转基因明胶酶A小鼠。最后，明胶酶A作为单独的药物诱导功能障碍的心室重构的能力将通过在心脏中的靶向基因表达在体内进行测试。这些研究应该为特定的基质金属蛋白酶在心脏损伤反应中的作用提供关键的见解，并为开发这种致残疾病的新治疗形式提供病理生理学基础。